Research on Anti-tumor Pharmacodynamics of Multi-functional Magnetic Lipid Polymer with Specific Targeted Transmission of siRNA and its Toxicity Evaluation.

introductionHepatocellular carcinoma (HCC) is the third leading cause of cancer deaths globally. Traditional treatments face limitations like low effectiveness, poor specificity, and significant side effects. Gene therapy, particularly siRNA-based, is promising for targeted gene regulation but requires effective delivery systems due to the instability and poor target delivery of unmodified siRNA.

methodsThis study examined the storage and biological stability of LP-PEI-SPION (LPS) and GPC3-LPPEI- SPION (GLPS). The potential of these agents as tumor imaging contrast agents and the targeting ability of gene delivery carriers were assessed through ex vivo organ fluorescence imaging and in vivo tumor magnetic resonance imaging (MRI). Antitumor efficacy was evaluated through tumor volume, protein blotting, immunohistochemistry, and TUNEL assays. In vivo safety was evaluated using HE staining, nude mouse weight changes, and blood biochemical indicators.

resultsLPS and GLPS both formed stable siRNA complexes. GLPS showed excellent tumor targeting in vivo. MRI results showed that the GPC3-targeting peptide effectively enhanced the MR imaging performance and diagnostic accuracy. Tumor volume and weight measurements demonstrated potent tumor inhibition by GLPS/ siRNA. Immunoblotting and immunohistochemistry revealed significant GPC3 reduction in the GLPS/siRNAtargeted group. Safety evaluations confirmed good biocompatibility for both LPS/siRNA and GLPS/siRNA. DISCUSSION: GLPS/siRNA demonstrates superior in vitro transfection and anti-tumor efficacy compared to LPS/siRNA. It exhibits high tumor fluorescence signals, reduced MRI T2 relaxation time, and effective tumor enrichment, providing MRI imaging capability. Safety assessments, including HE staining, body weight, and blood biochemistry, indicate good biocompatibility. The development of siRNA-based therapeutics has progressed, yet challenges remain, such as siRNA's susceptibility to degradation and poor membrane permeability. While carriers like liposomes and polymers are used, they have limitations. Nanoparticles that enhance endosomal/lysosomal escape and promote cytoplasmic siRNA release are needed to improve delivery efficiency, reduce off-target effects, and enhance safety.

conclusionGLPS/siRNA demonstrates good stability, tumor targeting, imaging capability, and antitumor efficacy with favorable safety, positioning it as a promising theragnostic platform for HCC. This integrated system provides novel clinical tools for diagnosis and treatment, establishes a foundation for clinical translation, and enables simultaneous tumor imaging and gene therapy-offering innovative strategies for combined tumor theranostics.